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Neurologists and infectious diseases physicians have much in common. There are not many of either; they share a love of the long differential diagnosis (preferably in Latin); but most importantly, both groups can suffer loss of confidence when confronted with a patient with an infected nervous system. As a result, these patients may find themselves falling between two pillars of expertise. This article aims to close the gap. We will resist temptation to present long lists of potential (but exceedingly rare and exciting) infectious agents. Instead, we will describe how to approach the infected patient, and how the common nervous system infections are recognised and treated. Readers should consult recent treatment guidelines for antibiotic doses and duration (see further reading and resources box).
General principles: how to approach an infected patient
Infectious disease practice differs from neurology in the need to consider the biology of two organisms: the bug as well as the patient. Junior physicians at the Hospital for Tropical Diseases in London are taught to ask: why did this person, from this place, get this disease, at this time? The question summarises the key considerations required to begin the diagnostic process, and is an elegant reminder that an infectious disease depends on the complex interaction between the virulence of the infectious agent, the susceptibility of the host and the nature of their shared environment (figure 1). This question can only be satisfactorily answered first by a well directed history (box 1)—whatever else, answers to the following two questions are essential:
▶ is the patient particularly susceptible to some or all infectious agents?
▶ what is the duration of illness?
Box 1 Key elements in the history: why did this person, from this place, get this disease, at this time?
▶ Immune suppressed or immune competent? (eg, pregnancy, drugs, splenectomy, cancer, HIV/AIDS)
▶ High risk sexual behaviour or intravenous drug use
▶ Vaccination/prophylaxis (eg, against malaria)
▶ Contact with infected individuals (eg, tuberculosis or chickenpox in family member)
▶ Duration of potential exposure to infection
▶ Travel (eg, to malarial or arbovirus endemic area)
▶ Season of exposure (eg, enterovirus infections commoner in summer/autumn)
▶ Animals (eg, cat scratches; tick, animal or mosquito bites)
▶ Food and water (eg, eating unpasteurised dairy products or fresh water swimming)
▶ Time from potential exposure to disease (eg, chickenpox, mumps, malaria)
▶ Duration of symptoms before presentation
▶ Duration and nature of any prior treatment (eg, antibiotics given prior to assessment)
To answer the first requires an enquiry spanning vaccination history, travel, illicit and immune suppressive drugs, and risk factors for HIV. Without answers to both questions it is almost impossible to construct a sensible differential diagnosis and management plan.
Infections involve the nervous system by:
▶ direct inoculation and interneuronal trafficking (eg, rabies, tetanus toxin)
▶ haematogenous dissemination (eg, Mycobacterium tuberculosis)
▶ contiguous spread from a site in communication with the nervous system (eg, otitis media leading to bacterial meningitis).
The examination should help determine which of these mechanisms is responsible. Evidence of any disease outside the nervous system is especially pertinent because it may indicate the mechanism of nervous system infection as well as suggest opportunities for diagnostic sampling (figure 2).
A summary of the key diagnostic tests for a range of common neurological infections is given in box 2. Many doctors (including infectious diseases physicians) consider the microbiology laboratory a black box to which specimens are sent and from which answers mysteriously appear. Like clinical medicine, there is art as well as science to traditional diagnostic microbiology. Its value depends on the quality of the specimens submitted and the human attributes of those who practise it. There are several ways to get the most out of your diagnostic laboratory (box 3) and good communication is essential.
Box 2 The key diagnostic tests for the common neurological infections
▶ Pyogenic bacteria (eg, agents of bacterial meningitis, abscess, subdural empyema)
▶ Mycobacterium tuberculosis
▶ Listeria monocytogenes
▶ Herpes viruses (HSV-1, -2; varicella zoster virus; cytomegalovirus; Epstein–Barr virus)
▶ Polyoma viruses (eg, JC virus)
▶ Toxoplamsa gondii
▶ Mycobacterium tuberculosis
CSF antigen tests
▶ Cryptococcus neoformans
Serology (detection of pathogen specific antibodies)
▶ Syphilis (blood and CSF)
▶ Lyme disease (blood)
▶ Epstein–Barr virus, mumps, flaviviruses (eg, Japanese encephalitis, West Nile) (blood)
▶ Toxocara canis/Toxoplasma gondii (blood)
▶ Schistosomiasis (blood)
Box 3 How to get the most from your diagnostic microbiology/virology laboratory
▶ Correct container for sample (eg, fluoride tube for CSF glucose)
▶ Sterile technique for blood cultures/CSF
▶ Baseline acute serum and plasma samples for storage
▶ Send adequate volumes of CSF (at least 8 ml if suspect tuberculosis)
Labelling and clinical information
▶ Check name, hospital number are correct on sample and form
▶ Include detailed clinical information such as exposure history and risk factors
▶ Ask your microbiologists/infectious disease physician which tests to send
▶ Speak directly to the technician performing the test; warn them of urgent samples
Finally, some infections pose a wider risk to the public and, in England and Wales, are notifiable by statute on suspicion to the local public health authorities (box 4).
Box 4 Neurological infectious diseases notifiable by Statute in England and Wales
▶ Acute encephalitis
▶ Acute meningitis
▶ Acute poliomyelitis
▶ Meningococcal septicaemia
Notification should be to the Local Authority Proper Officer, usually a consultant in communicable disease control. Notification should occur on suspicion and not be delayed for confirmatory microbiological tests.
A classification of nervous system infections
The duration of illness is essential in defining the likely cause of nervous system infections. We have subdivided them according to whether the duration is acute (<5 days), subacute (5–14 days) or chronic (>14 days duration). We have focused on early disease recognition and management. Recent review articles and treatment guidelines contain more detailed information (see further reading and resources box).
Acute nervous system infections
The onset of headache, fever and neck stiffness over a few hours should provoke one crucial question: could this be pyogenic bacterial meningitis? Even if the answer is only a qualified ‘yes’, a third generation cephalosporin (ceftriaxone or cefotaxime) should be prescribed immediately. While the drug is being prepared, blood should be taken for bacterial culture for Streptococcus pneumoniae and Neisseria meningitidis and for PCR. These investigations may prove enormously helpful if the lumbar puncture is delayed or impossible. A purpuric rash strongly suggests N meningitidis infection; the bacteria may be cultured from the skin lesions.
Lumbar puncture is an essential early investigation although it is often delayed by requests for brain imaging, and then sometimes more delay in getting the imaging. There is a common misperception, especially among junior clinicians, that lumbar puncture cannot be performed safely without the prior exclusion of a space occupying brain lesion or diffuse cerebral oedema. Whether brain imaging should be mandatory for this purpose before all emergency lumbar punctures excites diverse opinion among neurologists, but many recognise the following:
▶ brain imaging is not good at predicting those at risk of ‘coning’ following lumbar puncture
▶ imaging should precede lumbar puncture if the patient is immune compromised, comatose or has had recent seizures, papilloedema or focal neurological signs.
Lumbar puncture can be performed safely without prior brain imaging in young, immune competent, alert and orientated individuals without focal neurological signs or coagulopathy.
In the UK, ceftriaxone and cefotaxime are active against all strains of N meningitidis, Haemophilus influenzae and nearly all S pneumoniae. S pneumoniae strains resistant to ceftriaxone/cefotaxime are more common in the USA, Spain and parts of southern Africa, so unless a patient has recently lived in one of these regions, the immediate empirical addition of vancomycin is unnecessary.
Two further questions need immediate consideration:
▶ should adjunctive dexamethasone be given?
▶ is this patient at risk of infection with Listeria monocytogenes?
Whether dexamethasone improves outcome from bacterial meningitis remains uncertain. Dexamethasone may improve survival in HIV uninfected adults with confirmed bacterial meningitis (positive CSF Gram stain or culture) and it probably should be given to patients who conform to these characteristics (0.15 mg/kg every 6 h for 4 days). The findings (in rabbits) which indicated only preantibiotic corticosteroids improved outcome have not been substantiated in clinical trials. If corticosteroids benefit patients with bacterial meningitis, they probably do so if started up to 48–72 h after the first antibiotic dose.
L monocytogenes is a rare cause of bacterial meningitis and has innate resistance to cephalosporins. Ampicillin/amoxicillin is effective and should be given to immune suppressed patients with meningitis, including those who are pregnant and older patients (aged >50 years). Alert the laboratory if you are considering this diagnosis. L monocytogenes is a Gram positive rod, a characteristic shared by many benign skin bacteria; when isolated from blood and/or CSF it may be wrongly ignored as a contaminant.
In the UK, viruses cause more acute meningitis than bacteria; predominantly enteroviruses, herpes simplex viruses (HSV) 1 and 2 and (in the unvaccinated) mumps. Antiviral treatment is not required as long as there is no evidence of encephalitis (see below).
Distinguishing viral from bacterial meningitis can be difficult:
▶ <1000 leucocytes/mm3 in CSF
▶ predominance of lymphocytes in CSF
▶ CSF:plasma glucose >50%
These features suggest viral meningitis although partially treated bacterial meningitis has similar features. All of the common viral causes can be diagnosed by PCR on CSF.
If the cause of meningitis remains elusive, revisit the history, re-examine the patient and repeat the lumbar puncture; and consider rare causes of meningitis, or conditions with similar symptoms and signs (box 5). And remember, all patients with an unexplained neurological illness require an HIV test.
Box 5 Mimics and uncommon causes of acute infectious meningitis and encephalitis
Acute encephalitis can be infectious, postinfectious or immune mediated. In the majority (50–70%), no cause is found.
▶ HSV and varicella zoster virus (VZV) are the commonest infectious causes in the UK, although cytomegalovirus, human herpes virus type 6 and Toxoplasma gondii cause encephalitis in immune compromised patients.
▶ Worldwide, ARthropod-BOrne viruses (arboviruses), such as Japanese encephalitis and West Nile virus, cause significant numbers of cases, and rabies (which is invariably fatal) remains endemic in many countries.
▶ Measles virus and Mycoplasma pneumoniae are the commonest causes of postinfectious encephalitis.
Patients with acute encephalitis have fever, altered consciousness with or without seizures, and CSF pleocytosis, although these findings are not universal. It can be difficult to distinguish acute encephalitis from septic encephalopathy. The latter is a syndrome of brain dysfunction associated with systemic sepsis:
▶ the clinical features range from mild slowing of mentation and impairment of attention to coma
▶ neurological signs are usually symmetrical, such as paratonic rigidity
▶ asterixis, tremor and myoclonus are uncommon
▶ CSF abnormalities are unusual, except for mildly raised protein
▶ focal neurological signs, especially when lateralised, or seizures strongly suggest encephalitis.
Septic encephalopathy is a diagnosis of exclusion. Other mimics of acute encephalitis are given in box 5.
Aciclovir reduces death and disability from HSV encephalitis and should be prescribed empirically to all patients with suspected encephalitis until the cause has been determined.
Diffusion weighted MRI reveals early changes of HSV encephalitis, which typically affects the temporal lobes. CSF HSV PCR early (<48 h of symptoms) may be falsely negative; in this circumstance, aciclovir should be continued and CSF HSV PCR repeated. A negative HSV PCR after 72 h of symptoms has a high negative predictive value. In proven cases, treat with 14–21 days of aciclovir; beware of aciclovir induced renal toxicity. Adjunctive corticosteroids are not recommended.
Fever and travel to a malaria endemic region within the past 6 months should prompt an immediate blood film for malaria. Do not exclude the possibility of malaria if the patient took antimalarial prophylaxis: it is only 80–90% effective. Only Plasmodium falciparum causes cerebral malaria which is diagnosed on the basis of parasitaemia and coma. Neck stiffness is not a feature, and the CSF is normal if examined; plasmodium is never seen in CSF.
Treat cerebral malaria with intravenous quinine, or artesunate which is more effective but can only be obtained in the UK through specialist centres. Do not delay giving quinine while waiting for artesunate. Be aware that quinine can cause severe hypoglycaemia.
Brain abscess and subdural empyema
Staphylococcus aureus, many streptococci (eg, S pyogenes, S pneumoniae, S milleri) and some anaerobic bacteria (eg, Bacteriodes fragilis) are associated with pus and abscess formation (fig 3A). They can infect the brain parenchyma (cerebral abscess) or occur between the dura and arachnoid mater (subdural empyema) through penetrating traumatic injuries, neurosurgery, haematogenous seeding (eg, endocarditis) or contiguous spread (eg, mastoiditis). Right to left circulatory shunts increase the risk of brain abscesses. M tuberculosis can mimic all of the above infections.
Collections of pus cause swinging fever; when involving the brain they also cause headache and, depending on location, focal neurological deficits and seizures.
Abscess/empyema drainage is the key to rapid resolution; cure is affected more often by the surgeon's knife than the choice of antibiotic. Determining the cause of the infection is important, however: take pretreatment blood cultures and submit pus for staining and culture (including for M tuberculosis).
Community acquired brain abscesses should be treated with a third generation cephalosporin and metronidazole. If a haematogenous infection source is suspected (eg, S aureus bacteraemia) arrange an echocardiogram and search for any foci of extracranial infection.
Acute myelopathy can result from intrinsic or extrinsic cord pathology; it is a neurological emergency. The pyogenic bacteria described above are usually responsible for extrinsic compression; M tuberculosis must also be considered. Pus between the spinal dura mater and vertebral periosteum (spinal epidural abscess) causes localised back pain and tenderness followed by radicular symptoms, and finally myelopathy. S aureus accounts for >60% of epidural abscesses. Urgent excision and drainage may prevent permanent cord damage.
In the UK, intrinsic spinal cord inflammation (myelitis) is usually non-infectious, although postinfectious and postvaccine cases are well recognised. Infectious causes include HSV, VZV, M tuberculosis, syphilis and (rarely) parasites (eg, schistosomiasis) (fig 3C). CSF leucocytes and protein are usually raised and CSF should be sent for viral PCR. Send serological tests for syphilis, Mycoplasma pneumonia and Borrelia burgdoferi (Lyme disease).
Japanese encephalitis, West Nile and Coxsackie viruses can cause polio-like syndromes (acute flaccid paralysis). The last reported case of poliomyelitis in the UK was in 2000, caused by live oral polio vaccine reverting to wild type. Since 2004, only the killed vaccine has been used.
Acute peripheral nervous system infections
The commonest acute peripheral nervous system infection in the UK is herpes zoster, or shingles, caused by reactivation of VZV. VZV becomes latent in the ganglia of sensory and autonomic peripheral and cranial nerves following primary infection (chickenpox). Shingles is associated with reduced cell mediated immunity through ageing, drugs, malignancy or HIV infection, but most times there are no obvious risk factors.
▶ Patients typically experience tingling or pain in one or more dermatomes a few days before the appearance of a vesicular rash.
▶ Thoracic dermatomes are most commonly affected.
▶ 15% of cases affect areas innervated by cranial nerves, most frequently the ophthalmic division of the trigeminal nerve.
▶ Reactivation can occur without a rash but with the prodromal sensory symptoms: zoster sine herpete.
▶ Rare manifestations include segmental paralysis in the myotome corresponding to the rash, cranial neuropathies, polyradiculitis, myelitis and stroke.
Shingles is usually a clinical diagnosis but VZV can be demonstrated in the lesions by PCR. Immune competent patients are effectively treated with oral aciclovir or valaciclovir; intravenous therapy may be necessary in immune suppressed patients and those with sight threatening ophthalmic zoster. Antiviral treatment reduces the incidence of postherpetic neuralgia. The role of adjunctive corticosteroids is unclear; some advocate their use in older patients with severe neuritic pain at the onset of shingles. While steroids reduce the acute discomfort, they have not been demonstrated to prevent postherpetic neuralgia.
Toxin mediated disorders
There are 10–15 botulism cases and 5–10 tetanus cases annually in the UK; both are more common in injecting drug users, especially ‘skin poppers’ (who inject drugs into tissue). The clinical syndromes of botulism (descending flaccid paralysis) and tetanus (spasmodic rigidity) are caused by two closely related toxins released from Clostridium botulinum and Clostridium tetani, respectively. Both diseases arise from wounds infected with the bacteria; botulism can also follow the consumption of contaminated foods.
Tetanus is a clinical diagnosis. Patients experience muscle stiffness followed by generalised spasms. Laryngeal spasm can cause acute airway obstruction; tracheostomy must be considered early. Wounds should be debrided and the patient treated with metronidazole (to arrest toxin release) and specific antitetanus immune globulin (to neutralise circulating toxin). Spasms can be controlled with benzodiazepines. Autonomic dysfunction (fluctuating heart rate, blood pressure and temperature) is maximal in the second week of the illness and may be controlled with magnesium infusions. Survivors must be vaccinated before discharge—disease does not confer natural immunity.
Botulism is diagnosed clinically by a descending flaccid paralysis which starts in the muscles supplied by the cranial nerves; autonomic nervous system dysfunction is common, manifest as dry mouth and postural hypotension. A mouse bioassay can detect toxin in serum. The toxin uses the ganglioside GQ1b to gain entry to neurons; hence botulism may mimic Miller Fisher syndrome which is associated with an autoantibody to GQ1b. Suspected botulism should be discussed with the UK Health Protection Agency (http://www.hpa.org.uk/) who will provide advice about the bioassay and treatment with botulinum equine antitoxin.
Subacute nervous system infections
The possible causes of subacute and chronic nervous system infections very much depend on the immune status of the patient. An HIV test is an essential early investigation.
Tuberculosis is the most important cause of subacute meningitis in the UK and worldwide, regardless of immune status. It is also the hardest to diagnose and treat. Death or severe neurological disability are strongly associated with treatment delay yet there is no single laboratory test that will reliably make or exclude the diagnosis. In many cases treatment must be started and continued on the basis of compatible clinical features (box 6).
▶ The diagnostic yield of CSF Ziehl–Neelsen stain and culture for M tuberculosis increases with the volume of CSF submitted; take at least 8 ml for these tests alone and discuss your diagnostic requirements with the laboratory (box 3).
▶ Clinical or radiological evidence of extraneural tuberculosis may allow further diagnostic specimens.
▶ Isolation of an organism is essential to determine bacterial drug susceptibility.
Box 6 The diagnostic features of tuberculous meningitis
▶ >5 days of symptoms
▶ Non-specific prodrome; slowly worsening headache, vomiting; progression to coma
▶ Recent tuberculosis contact (more helpful in children)
▶ Neck stiffness may not be prominent
▶ Cranial nerve palsies in 30% (VI > III > IV > VII)
▶ Hemiplegia in 20%
▶ May have signs of extraneural tuberculosis (50%)
▶ Blood: low plasma sodium (70%)
▶ CSF: leucocytes 5–1000/mm3; protein 45–250 mg/dl (>2000 if cord involvement); CSF:plasma glucose <0.5 (in 95%)
▶ Acid fast bacilli seen in CSF in 10–70% (depending on volume of CSF examined)
▶ Mycobacterium tuberculosis cultured from CSF in 30–80% (depending on volume of CSF cultured)
▶ PCR: sensitivity around 55%; specificity 95–100%
▶ CT/MRI: exudates in basal cisterns, hydrocephalus, infarcts (basal ganglia), tuberculomas (ring enhancing lesions)
Treat tuberculous meningitis with four antituberculosis drugs and dexamethasone. Rifampicin, isoniazid and pyrazinamide should be given with a fourth drug—usually ethambutol—to cover the possibility of isonaizid resistant bacteria (5% in the UK); it adds little to the intracerebral activity of the other drugs in drug susceptible disease.
Six to eight weeks of adjunctive dexamethasone (starting at 0.4 mg/kg/day and reducing gradually to stop over 8 weeks) improves survival. HIV associated tuberculous meningitis should receive the same treatment regimen although the benefit of corticosteroids is uncertain and there are important interactions between rifampicin and antiretroviral (ARV) drugs (see further reading and resources box for more details).
Patients often get worse before they get better, commonly due to hydrocephalus, cerebral infarction, expanding tuberculoma and hyponatraemia. Drug resistance should be suspected early in those previously treated for tuberculosis. Never change the antituberculosis regimen without consulting local tuberculosis experts.
Syphilis is caused by Treponema pallidum and is making a comeback in the UK, especially in homosexual men with HIV. It can be acquired congenitally or through sexual intercourse. The sexually acquired disease is divided into primary, secondary, early latent (<2 years infection) and late latent (>2 years infection), and tertiary syphilis. The neurological manifestations include subacute meningitis and radiculomyelitis in secondary syphilis, and dementia (general paralysis of the insane), tabes dorsalis and intracerebral gumma in tertiary syphilis.
▶ Serological tests identify treponemal specific antibodies: syphilis IgG and IgM, T pallidum haemagglutination assay (TPHA) and T pallidum particle agglutination assay (TPPA).
▶ Indirect serological tests indicate disease activity; Venereal Disease Reference Laboratory (VDRL) test or Rapid Plasma Reagin (RPR) test.
▶ Patients with suspected neurosyphilis should have their CSF examined; a positive CSF VDRL or RPR confirms neurosyphilis but a negative result does not exclude it (CSF VDRL/RPR is negative in approximately 10% of symptomatic disease).
▶ A negative CSF treponemal specific test (TPHA or TPPA) excludes neurosyphilis.
Neurosyphilis should be treated with 17 days of either intramuscular procaine penicillin with probenicid or benzylpenicillin. Adjuvant prednisolone (40–60 mg/day for 3 days) started 24 h prior to antibiotics is recommended to prevent the Jarisch–Herxheimer reaction.
Cryptococcus neoformans is a yeast which causes subacute or chronic meningitis in patients with impaired cell mediated immunity, most commonly through advanced HIV disease (blood CD4 count <200 cells/mm3). Occasionally, it causes meningitis in immune competent individuals, usually with a more virulent subspecies (C neoformans var Gatti).
Clinically, the disease is indistinguishable from tuberculous meningitis. However, the yeast can be seen easily in CSF by India Ink staining, and cultured, and there is a highly sensitive and specific crytococcal antigen test on blood and CSF.
Management revolves around killing the yeast, relieving any raised intracranial pressure and hydrocephalus, and addressing, if possible, the underlying immune suppression:
▶ Kill the yeast with amphotericin B (the liposomal formulation is less nephrotoxic) and flucytosine (although the contribution of flucytosine remains debated).
▶ After 2 weeks, or once the CSF is sterile, treat with oral fluconazole for a further 8 weeks. If the patient remains severely immune suppressed, lifelong low dose fluconazole may be required.
▶ There is little evidence to determine optimal management of raised intracranial pressure. CSF manometry is essential at the start of treatment to determine whether repeated, sometimes daily, therapeutic lumbar punctures are required to lower the pressure. Serial lumbar punctures are indicated if the CSF opening pressure is >25 cm H2O; the opening pressure should be reduced to <20 cm H2O or 50% of the initial pressure. Repeat lumbar punctures daily until the pressure is stable. Consider a lumbar drain or ventriculo-peritoneal shunt if the patient deteriorates despite these measures.
▶ Adjunctive corticosteroids or acetozolamide do not help.
Without correction of the immune deficit the outlook for many patients is bleak. If HIV infected, current UK guidelines suggest starting ARV drugs after 2 weeks of antifungal therapy although subsequent immune reconstitution can cause aseptic meningitis and space occupying lesions.
Parasitic nervous system infections
Parasitic infections should be considered if the absolute number of eosinophils in blood is >0.4×109 cells/l (absolute count is more important than the percentage) or if any eosinophils are found in the CSF. These infections are rare in the UK; with the exceptions of toxoplasmosis in immune suppressed patients and Toxocara canis in children, they generally occur in those who have lived in or travelled to tropical regions.
Cysticercosis is globally the most important parasitic brain disease. It is caused by disseminated infection with the pork tapeworm (Taenia solium). The disease is contracted following ingestion of food and water contaminated with T solium eggs, not through the consumption of contaminated pork (therefore, non-pork eaters can get cysticercosis). The larvae migrate to the brain and eye and form cysts, the former commonly resulting in epilepsy. Massive cerebral invasion can result in encephalitis. Diagnosis relies on compatible epidemiological and neuroradiological (multiple ring enhancing lesions) and serum and CSF findings. Treatment is with albendazole (for 7 days or more) and adjunctive dexamethasone if there are multiple lesions.
T canis can be contracted in the UK, usually by children ingesting contaminated dog faeces. The migrating worms affect the eye (ocular larva migrans) and rarely the brain, causing an eosinophilic meningoencephalitis. Serological tests confirm the diagnosis.
In tropical regions, Angiostronglus cantonensis and Gnathostoma spingerum cause eosinophilic meningitis following consumption of their poorly cooked intermediate hosts (eg, snakes, fish, crabs, frogs, snails) (fig 3D). A careful gastronomic and travel history is required to make the diagnosis; serological tests are unhelpful.
Trypanosomes cause acute and chronic neurological disease (sleeping sickness) in sub-Saharan Africa and are occasionally acquired by travellers to this region. Trypanosoma brucei rhodesiense causes disease in East Africa and T brucei gambiense in West Africa; both are transmitted by tsetse fly bites.
▶ East African trypanosomiasis presents acutely with painful lymphadenitis in the region of the bite (sometimes with a chancre), followed by encephalitis. Diagnosis is by microscopic demonstration of the parasites in lymph node aspirates and blood. CSF examination is essential to determine neurological involvement. Treatment of extraneural disease is with suramin, with the addition of melarsoprol if there is neurological involvement.
▶ West African (T gambiense) neurological disease is more indolent and can mimic dementia, appearing months to years following infection.
Chronic nervous system infections
The neurological complications of HIV may be caused by the virus, opportunistic infections or ARV drug toxicity. The direct neurological effects of HIV infection are acute or chronic.
▶ HIV seroconversion can cause acute meningitis, encephalitis or Guillain–Barré syndrome.
Chronic HIV infection can result in problems in the brain, cord and peripheral nerves:
– HIV associated neurocognitive disorders are an increasingly recognised consequence of chronic HIV infection, their spectrum extending from subtle cognitive deficits to dementia.
– HIV infection can cause spinal vacuolar myelopathy, characterised by progressive lower limb weakness, spasticity, urinary urgency and incontinence; it generally occurs late in advanced, untreated HIV and can improve with ARVs.
– A distal sensory peripheral neuropathy affects up to 70% of HIV patients. Distinguishing HIV driven neuropathy from ARV associated toxic neuropathy may only be possible by establishing whether symptoms preceded or followed ARV treatment. Both are painful and associated with hyperalgesia or allodynia; in neither are proprioceptive abnormalities or weakness common. The drugs most often associated with toxic neuropathy—d4t (stavudine), ddC (zalcitabine) and ddI (didanosine)—are no longer commonly used in the UK. Neurophysiological studies can reveal length dependent axonal changes and impaired thermal thresholds in both neuropathies. HIV neuropathy is treated by viral suppression whereas ARV associated toxic neuropathy requires removal of the causal drug.
– HIV headache is a subacute complaint reported in patients with advanced disease. It is a diagnosis of exclusion; opportunistic infections as well as other secondary headache causes should be assiduously sought. It may be due to low level HIV driven aseptic meningitis. It is less common since the advent of ARVs.
ARVs have dramatically reduced the incidence of neurological opportunistic infections in the UK. Box 7 presents the infections and other diagnoses to consider, relative to CD4 count:
▶ Tuberculosis and cryptococcal meningitis are discussed above.
▶ Toxoplasmosis typically presents with seizures and one or more space occupying lesions with significant surrounding oedema. Serological tests indicate prior toxoplasma infection but do not confirm active cerebral infection. CSF PCR can be helpful but lumbar puncture may not be safe. Diagnosis often depends on clinical and neuroradiological response to 2 weeks of treatment with pyrimethamine and sulphadiazine. Tuberculosis and malignancy are the major differential diagnoses.
▶ Progressive multifocal leucoencephalopathy is a chronic demyelinating disease caused by JC virus and is nearly always associated with severe immune suppression. Other than advanced HIV, it has been described in patients taking natalizumab, rituximab and alemtuzumab. Progressive multifocal leucoencephalopathy affects the brain white matter, rarely the spinal cord and never the optic nerves. Diagnosis is through CSF JC virus DNA detection by PCR or sometimes by brain biopsy. In all cases, treatment is through relieving the immune suppression.
▶ Patients starting ARVs may experience new or worsening neurological symptoms. This may be due to immune reconstitution inflammatory syndrome or unmasking of subclinical opportunistic infections. The latter must be vigorously sought. Corticosteroids may relieve the symptoms of the immune reconstitution inflammatory syndrome.
Box 7 Neurological complications of HIV
Human T cell lymphoma virus
Human T cell lymphotropic virus type 1 (HTLV-1) causes progressive myelopathy (HTLV-1 associated myelopathy/tropical spastic paraparesis), predominantly in the Far East, Middle East, Caribbean, sub-Saharan Africa and South America. Transmission is usually from mother to child. Less than 3% of seropositive individuals develop neurological disease, characterised by onset in the fourth decade of gradual progressive spastic lower limb weakness, prominent bladder dysfunction and minor sensory signs often including lower back pain with radicular symptoms. There are no established antiviral or immunosuppressive therapies; some advocate steroids early in the disease process.
Subacute sclerosing panencephalitis
Subacute sclerosing panencephalitis occurs 6–10 years after primary measles infection. It is characterised by progressive cognitive decline, seizures, myoclonus, ataxia, choreoathetoid movements and rigidity. Brain MRI shows widespread T2 hyperintense lesions affecting both grey and white matter. EEG may reveal characteristic periodic complexes. Raised CSF measles specific antibody concentration confirms the diagnosis.
Lyme disease is caused by Borrelia burgdorferi, a multisystem tickborne disorder endemic in forested areas of North America, Europe and Asia. A rash (erythema migrans) can occur at the site of inoculation, and the bacteria may disseminate to the nervous system. Cranial nerve lesions (especially VIIth nerve), lymphocytic meningitis, radiculitis, peripheral neuropathy and rarely encephalitis may occur weeks to months after the initial infection. A later (but very rare) complication is chronic progressive encephalomyelitis, which mimics multiple sclerosis. Treat neurological Lyme disease with ceftriaxone/cefotaxime.
Overdiagnosis based on non-specific serological tests has been a problem. International guidelines now recommend that positive screening tests must be confirmed by western blot.
Whipple's disease (caused by Tropheryma whipplei) is a rare multisystem granulomatous disease. Ten to forty per cent of patients have neurological features, including dementia, disorders of eye movements (particularly vertical supranuclear ophthalmoplegia), myoclonus and hypothalamic dysfunction. The diagnosis is made by demonstrating T whipplei in CSF by PCR (sensitivity around 50%) and/or finding the organism in small bowel biopsies.
Leprosy (caused by Mycobacterium leprae) affects skin, peripheral nerves and eyes.
▶ Tuberculoid leprosy is characterised clinically by hypopigmented anaesthetic skin lesions, thickened peripheral nerves and mononeuropathies (fig 3B); and pathologically by granuloma formation but few bacteria.
▶ Lepromatous disease is characterised clinically by thickening of the skin (often around the face) and a ‘glove and stocking’ neuropathy; and pathologically by a few granulomas but numerous bacteria.
▶ Most patients have intermediate forms of the disease.
Intradermal acid fast bacilli on skin smears confirm the diagnosis but are positive in only 30% of patients. The bacteria cannot be cultured in the laboratory. Skin or sensory nerve biopsy can aid diagnosis. Antibiotic treatment is highly effective at killing bacteria but may not arrest nerve damage driven by immune response to dead bacteria. Corticosteroids, and sometimes thalidomide, may alleviate symptoms.
▶ When approaching the patient ask yourself: why did this person, from this place, get this disease, at this time?
▶ Duration of history and immune status are critical to determining the possible infective agents.
▶ To get the most out of laboratory diagnostic tests, keep in regular, friendly communication with the laboratory staff.
▶ Bacterial meningitis, tuberculous meningitis and HSV encephalitis are medical emergencies: do not delay antimicrobial therapy by waiting for laboratory diagnostic confirmation.
▶ Everyone with a suspected or confirmed neurological infection should be offered an HIV test.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.
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